NMDA receptors are a subtype of glutamate-gated ion channels that mediate excitatory synaptic transmission between neurons in the central nervous system (Dingledine, R. et al., [1999], “The glutamate receptor ion channels,” Pharmacological Reviews 51:7-61). NMDA receptors are a subtype of the most widespread excitatory neurotransmitter receptor in the brain. Excessive activation of NMDA receptors kills neurons, and current evidence implicates NMDA receptor activation in a variety of neurologic disorders that include epilepsy, ischemic brain damage, traumatic brain/spinal cord injury, and Alzheimer's Diseases, Huntington's chorea and Amyotrophic Lateral Sclerosis (ALS).
In animal models of stroke and brain trauma, glutamate released from affected neurons can overstimulate NMDA receptors, which in turn causes neuronal death. Because overactivation of NMDA receptors is neurotoxic, compounds that block NMDA receptors have been considered candidates for treatment of stroke or head injuries. Numerous animal studies have validated NMDA receptors as targets for neuroprotection in stroke, brain and spinal cord trauma, and related settings that involve brain ischemia. NMDA receptor blockers are effective in limiting the volume of damaged brain tissue in experimental models of stroke and traumatic brain injury. (Choi, D. (1998), “Antagonizing excitotoxicity: A therapeutic strategy for stroke,” Mount Sinai J. Med. 65:133-138; Dirnagle, U. et al. (1999) “Pathobiology of ischaemic stroke: an integrated view,” Tr. Neurosci. 22:391-397; Obrenovitch, T. P. and Urenjak, J. (1997) “Is high extracellular glutamate the key to excitotoxicity in traumatic brain injury,” J. Neurctrauma 14:677-698.) In addition, NMDA receptor antagonists are known to be anti-convulsant in many experimental models of epilepsy (Bradford, H. R. [1995] “Glutamate, GABA, and Epilepsy,” Progress in Neurobiology 47:477-511; McNamara, J. O. [2001] Drugs effective in the therapy of the epilepsies. In Goodman & Gliman's: The pharmacological basis of therapeutics [Eds. J. G. Hardman and L. E. Limbird] McGraw Hill, New York). However, dose-limiting side effects have thus far prevented clinical use of NMDA receptor antagonists for these neurologic conditions (Muir, K. W. and Lees, K. R. [1995] “Clinical experience with excitatory amino acid antagonist drugs,” Stroke 26:503-513; Herrling, P. L., ed. [1997] “Excitatory amino acid—clinical results with antagonists” Academic Press; Parsons, C. G. et al. [1998] “Glutamate in CNS disorders as a target for drug development: an update,” Drug News Perspective 11:523-569), and consequently enthusiasm for this receptor protein as a drug target has diminished within the pharmaceutical industry. NMDA receptor blockers also act synergistically with L-DOPA to relieve symptoms of Parkinsonism. In addition, such compounds are useful for treating chronic neuropathic pain and bipolar disorder. However, the first three generations of NMDA receptor antagonists (channel blockers, competitive blockers of the glutamate or glycine agonist sites, and noncompetitive allosteric antagonists) have not proved useful clinically.
Several recent papers have suggested that rapidly-growing brain gliomas can kill adjacent neurons by secreting glutamate and overactivating NMDA receptors The dying neurons make room for the growing tumor, and may release cellular components that stimulate tumor growth. These studies shown NMDA receptor antagonists can reduce the rate of tumor growth in vivo as well as in some in vitro models. (Takano, T., et al. (2001), “Glutamate release promotes growth of malignant glioma,” Nature Medicine 7:1010-1015; Rothstein, J. D. and Bren, H. (2001), “Excitotoxic destruction facilitates brain tumor growth,” Nature Medicine 7:994-995; Rzeski, W., et al. (2001), “Glutamate antagonists limit tumor growth,” Proc. Nat'l Acad. Sci 98:6372-6377.)
In the late 1980's a new class of NMDA receptor antagonists (phenylethanolamines) was discovered which did not bind at the agonist binding sites. This class, exemplified by the compound ifenprodil, selectively interacts with NMDA receptors containing the NR2B subunit. These compounds have exhibited neuroprotective properties in preclinical models. This class of antagonist lacks the severe side-effect liability of other types of NMDA antagonists (e.g. PCP-like psychotic symptoms and cardiovascular effects).
One of the most prevalent subtypes of NMDA receptor which contains the NR2B subunit has the unusual property of being normally inhibited by protons by about 50% at physiological pH (Traynelis, S. F. and Cull-Candy, S. G. [1990] “Proton inhibition of N-methyl-D-aspartate receptors in cerebellar neurons,” Nature 345:347-350. We have found that phenylethanolamines, typified by ifenprodil and CP101,606 inhibit activation of NMDA receptors by potentiating allosteric inhibition mediated by protons. In turn, small reduction of pH in the physiological range increases the potency of some phenylethanol-amines as NMDA receptor antagonists. The potency of ifenprodil for inhibition of NR2B subunit-containing recombinant NMDA receptors is enhanced at pH 6.8 compared to pH 7.5. (Mott et al. [1998], “Phenylethanolamines inhibit NMDA receptors by enhancing proton inhibition,” Nature Neuroscience 1(8):659-667.) Ischemic brain tissue, as well as the site of seizure generation in epilepsy, is characterized by a lower pH than is found in brain tissue.
Therapeutic compounds for the foregoing pathologies may have toxic side effects. It is thus an object of this invention to provide compounds which have enhanced activity under the lower pH conditions characteristic of such pathologies, and which are less active under the normal pH conditions of healthy brain tissue.
A number of patents discuss NMDA receptor antagonists, including U.S. Pat. No. 6,080,743 to Acklin et al.; U.S. Pat. Nos. 4,924,008 and 4,957,909 to Abou-Gharbia et al.; U.S. Pat. Nos. 5,889,026, 5,952,344, 6,071,929, 6,265,426, and 6,339,093 to Alanine et al.; U.S. Pat. No. 5,633,379 to Allgeier; U.S. Pat. Nos. 5,922,716, 5,753,657 and 5,777,114 to Aloup et al.; U.S. Pat. No. 5,124,319 to Baudy et al.; U.S. Pat. No. 5,179,085 to Bigge et al.; U.S. Pat. No. 5,962,472 to Bourson et al.; U.S. Pat. Nos. 5,919,826, 6,007,841, 6,054,451, and 6,187,338 to Caruso et al.; U.S. Pat. Nos. 5,498,610, 5,594,007, 5,710,168, and 6,258,827 to Chenard et al.; U.S. Pat. Nos. 5,888,996 and 6,083,941 to Farb; U.S. Pat. No. 5,981,553 to Farr et al.; U.S. Pat. Nos. 5,866,585, 6,057,373, and 6,294,583 to Fogel; U.S. Pat. No. 6,274,633 to Franks et al.; U.S. Pat. No. 5,385,947 to Godel et al.; U.S. Pat. No. 6,034,134 and 6,071,966 to Gold et al.; U.S. Pat. No. 5,714,500 to Griffith et al.; U.S. Pat. Nos. 5,563,157 and 5,606,063 to Harrison et al.; U.S. Pat. No. 5,395,822 to Izumi et al.; U.S. Pat. No. 5,118,675 to Jirkovsky et al.; U.S. Pat. No. 6,177,434 to Kopke et al.; U.S. Pat. No. 5,132,313 to Kozikowski et al.; U.S. Pat. Nos. 5,321,012, 5,502,058, 5,556,838, 5,654,281, 5,834,479, 5,840,731, 5,863,922, and 5,869,498 to Mayer et al.; U.S. Pat. Nos. 5,318,985, 5,441,963 and 5,489,579 to McDonald et al.; U.S. Pat. No. 6,284,776 to Meltzer; U.S. Pat. No. 6,180,786 to Metz, Jr.; U.S. Pat. No. 5,783,572 to Mowbray et al.; U.S. Pat. No. 6,200,990 to Namil et al.; U.S. Pat. No. 5,783,700 to Nichols et al.; U.S. Pat. Nos. 5,034,400, 5,039,528, 5,474,990, 5,605,911, 5,616,580, 5,629,307, 5,767,130, 5,834,465, 5,902,815, 5,925,634, and 5,958,919 to Olney et al.; U.S. Pat. No. 5,990,126 to Park et al.; U.S. Pat. No. 5,013,540 to Redburn; U.S. Pat. No. 6,025,369 to Rosenquist et al.; U.S. Pat. Nos. 5,106,847, 5,189,054 5,491,153, 5,519,048 5,675,018, and 5,703,107 to Salituro et al.; U.S. Pat. No. 6,096,743 to Shishikura et al.; U.S. Pat. No. 6,242,456 to Shuster et al.; U.S. Pat. No. 6,194,00 to Smith et al.; U.S. Pat. No. 6,197,820 to Sontheimer et al.; U.S. Pat. No. 5,385,903 to Steppuhn et al.; U.S Pat. No. 5,710,139 to Swahn; U.S. Pat. No. 5,192,751 to Thor; U.S. Pat. No. 5,614,509 to Turski et al.; U.S. Pat. Nos. 4,906,779, 5,093,525, 5,190,976, 5,262,568, 5,336,689, 5,559,154, 5,637,622, 5,767,162, 5,798,390, and 6,251,948 to Weber et al.; U.S. Pat. Nos. 5,095,009 5,194,430, 5,326,756, 5,470,844, and 5,538,958 to Whitten; U.S. Pat. No. 6,284,774 to Wright et al.; U.S. Pat. Nos. 5,587,384 and Re 36,397 to Zhang et al.; and U.S. Pat. No. 4,994,467 to Zimmerman. However, NMDA receptor blockers are needed which are enhanced at low pHs characteristic of certain pathological conditions for treatment of such pathological conditions.
All publications referred to herein are incorporated by reference to the extent not inconsistent herewith.